Interleukin (IL)-33 and the IL-1 Family of Cytokines—Regulators of Inﬂammation and Tissue Homeostasis

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Ajithkumar Vasanthakumar1,2 and Axel Kallies1,2,3

1Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia 2The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia 3The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria 3000, Australia Correspondence: [email protected]

Cytokines play an integral role in shaping innate and adaptive immune responses. Members of the interleukin (IL)-1 family regulate a plethora of immune-cell-mediated processes, which include pathogen defense and tissue homeostasis. Notably, the IL-1 family cytokine IL-33 promotes adaptive and innate type 2 immune responses, confers viral protection and facilitates glucose metabolism and tissue repair. At the cellular level, IL-33 stimulates differentiation, maintenance, and function of various immune cell types, including regulatory T cells, effector CD4+ and CD8+ T cells, macrophages, and type 2 innate lymphoid cells (ILC2s). Other IL-1 family members, such as IL-1β and IL-18 promote type 1 responses, while IL-37 limits immune activation. Although IL-1 cytokines play critical roles in immunity and tissue repair, their deregulated expression is often linked to autoimmune and inflammatory diseases. Therefore, IL-1 cytokines are regulated tightly by posttranscriptional mechanisms and decoy receptors. In this review, we discuss the biology and function of IL-1 family cytokines, with a specific focus on regulation and function of IL-33 in immune and tissue homeostasis.

nterleukin (IL)-1 family cytokines are potent sky 2014). However, IL-1 family cytokines also Iinitiators and amplifiers of immune responses play critical roles in facilitating tissue repair and and inflammation. Because they are secreted by preserving homeostasis. Thus, expression of IL- damaged cells and are crucial for eliciting in- 1 family members is tightly regulated at multiple flammatory responses, these cytokines are also levels, including transcriptional and posttrans- called “alarmins.” Deregulated expression of IL- lational mechanisms as well as the expression of 1 family members aggravates inflammation, decoy and antagonist receptors (Garlanda et al. autoimmunity, and allergic responses. Conse- 2013). IL-1 family cytokines can also function as quently, IL-1 blockade is used for the treatment nuclear factors and influence gene expression by of a variety of inflammatory diseases, including interacting with transcription factors or the rheumatoid arthritis, psoriasis, arthrosclerosis, chromatin (Martin and Martin 2016). IL-1 fam- ischemia, and reperfusion and graft rejection ily members also act as RNA-splicing factors to (Garlanda et al. 2013; Jesus and Goldbach-Man- regulate the expression of genes that are involved

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A. Vasanthakumar and A. Kallies

in diverse physiological roles, which include (TLRs) or by damaged cells undergoing necrosis survival and thermogenesis (Pollock et al. (Sims and Smith 2010). IL-33 was first identified 2003; Odegaard et al. 2016). as a nuclear factor expressed in high endothelial IL-33 is a prominent member of the IL-1 venules of the human Peyer’s patches, tonsils, family, which was discovered in 2003 (Baekke- and lymph nodes (Baekkevold et al. 2003). It vold et al. 2003) after more than two decades of was later found to be produced by endothelial search to identify a ligand for the orphan IL-1 and epithelial cells and by some hematopoietic receptor ST2 (Tominaga 1989). IL-33 was first cell types, including dendritic cells (Schmitz recognized for its critical role in the induction of et al. 2005), mast cells (Hsu et al. 2010), and allergic asthma by coordinating the expansion macrophages (Fock et al. 2013). IL-33 protein and function of adaptive and innate immune is constitutively expressed in astrocytes and oli- cells (Hardman and Ogg 2016). Consistent godendrocytes within the central nervous sys- with this notion, genome-wide association stud- tem (CNS); however, its expression and secre- ies (GWAS) have implicated polymorphisms in tion is elevated upon CNS injury (Yasuoka et al. IL-33 or its receptor ST2 (IL1RL1) in a range of 2011; Gadani et al. 2015). High expression of IL- diseases that includes asthma, cardiovascular 33 was also found in endothelial cells of various diseases, and allergy (Hardman and Ogg 2016). tissues, including the adipose tissue, liver, ova- More recently, however, novel roles for IL-33 ries, vagina, skin, lung, stomach, and salivary were uncovered that extend beyond immunity. gland (Villaret et al. 2010; Lopetuso et al. 2012; Forexample, IL-33 was identified to playa prom- Pichery et al. 2012; Byers et al. 2013; Carlock inent role in adipose tissue homeostasis, where it et al. 2014). In steady state, IL-33 is found pre- facilitates the expansion of anti-inflammatory dominantly in the nucleus of these cells with no immune cells, including type 2 innate lymphoid evidence of cytoplasmic localization. Inflamma- cells (ILC2)s and regulatory T (Treg) cells, there- tion induces IL-33 expression in epithelial cells, by suppressing obesity-induced inflammation but only tissue damage is thought to result in and preserving insulin sensitivity (Brestoff et al. efficient IL-33 release (Martin and Martin 2015; Lee et al. 2015; Vasanthakumaret al. 2015). 2016). Similarly, expression of IL-33 is height- Similar functions in repair and maintenance of ened in the liver during lipopolysaccharide nonlymphoid tissues werealsodescribed foroth- (LPS)-induced endotoxin shock, and in the er tissues such as the colon or injured muscle lung alveoli during papain-induced allergic tissue (Burzyn et al. 2013b; Schiering et al. airway inflammation (Pichery et al. 2012). A 2014; Kuswanto et al. 2016). IL-33 therefore similar phenomenon was observed in colonic plays critical and context-specific roles in lym- epithelium where IL-33 expression increased af- phoid and nonlymphoid tissues by preserving ter inflammation and injury (Schiering et al. tissue homeostasis or mediating inflammation. 2014) and in retinal Müller cells during macular This review focuses on the multifaceted func- degeneration (Xi et al. 2016). IL-33 can be de- tions of IL-33; however, we will also discuss the tected in the serum of patients with inflamma- biology of other IL-1 family cytokines. tory diseases or cancer and can potentially be used as a diagnostic and prognostic marker for a range of diseases, including hepatitis B infec- SOURCES OF IL-33 AND OTHER IL-1 FAMILY tion (Wang et al. 2012), psoriasis (Mitsui et al. CYTOKINES 2016), acute ischemic stroke (Qian et al. 2016), The IL-1 family consists of 11 members with and non-small-cell lung cancer (Hu et al. 2013). diverse and complex functions (Garlanda et al. Similar to IL-33, other members of the IL-1 2013). Most members of this family are ex- family are produced by a variety of hematopoi- pressed constitutively as full-length isoforms in etic and nonhematopoietic cells. Full-length IL- a wide range of hematopoietic and nonhemato- 1α protein is expressed constitutively in healthy poietic cells, but are only processed and released epithelial cells of the intestine, kidney, liver, en- by cells stimulated through Toll-like receptors dothelial cells, and astrocytes (Sims and Smith

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IL-33 and IL-1 Families of Cytokines

2010). Sterile inflammation caused by tissue in- IL-33 AND T HELPER (Th)2 RESPONSES jury facilitates the release of IL-1α, aiding the recruitment of macrophages to the injured site, Extracellular pathogens such as helminths and which may augment tissue damage (Rider et al. nematodes induce a Th2-type inflammation 2011). In contrast, during programmed apopto- mediated by the cytokines IL-4 and IL-5. IL-33 sis, IL-1α is retained in the nucleus to prevent was originally classified as a Th2 cytokine owing tissue damage (Cohen et al. 2010). In macro- to its role in amplifying type 2 immune re- phages, de novo synthesis of IL-1α occurs after sponses and exacerbating allergic asthma. This stimulation with LPS (Arango Duque and Des- idea was supported by the finding that expres- coteaux 2014). IL-1β is produced predominantly sion of IL-33 receptor ST2 appeared to be re- by cells of the hematopoietic compartment, in- stricted to the Th2 lineage (Lohning et al. 1998). cluding macrophages, blood monocytes, and Indeed, IL-33 stimulation increases IL-5 and IL- dendritic cells. In contrast to IL-1α, which is 13 but not IL-4 secretion by Th2 cells (Kurow- largely constitutively expressed, transcription of ska-Stolarska et al. 2008). In line with this find- Il1b is induced by components of the comple- ing, Th2 cells expressing ST2 secrete IL-5 and ment system, tumor necrosis factor (TNF), TLR are highly pathogenic (Endo et al. 2015). Con- ligands, and IL-1β itself (Sims and Smith 2010). sistent with a central role in Th2 responses, ST2 IL-18 is produced by two major immune cell was indispensable for Th2 responses in specific populations, macrophages, and dendritic cells helminth infection models (Hoshino et al. (Dinarello et al. 2013). However, stromal cells, 1999). Notably, IL-33 also acts as a chemoattrac- including endothelial cells, keratinocytes, and tant for human Th2 cells (Komai-Koma et al. intestinal epithelial cells constitutively express 2007). the IL-18 precursor (Dinarello et al. 2013). Sim- In addition to Th2 cells, ILC2s play a key role ilar to IL-1β and IL-33, mature IL-18 is released in promoting airway inflammation. They ex- from tissues undergoing necrosis (Mommsen press high amounts of ST2 and are exquisitely et al. 2009). IL-36 is expressed in several tissues, responsive to IL-33, which induces secretion of including skin, gut, lung, keratinocytes, and IL-5 and IL-13 (Moro et al. 2010; Neill et al. brain, and in some hematopoietic cells, includ- 2010). IL-33 administration expands the lung ing macrophages, neutrophils (Bozoyan et al. ILC2s, leading to airway hyperresponsiveness 2015), and T cells (Vigne et al. 2011). Similar (Moro et al. 2010; Barlow et al. 2012). RORα- to other IL-1 family members, IL-36 expression deficient mice, which lack ILC2, were unable to can be up-regulated by inflammatory stimuli, initiate Th2 responses when treated with papain including LPS. In skin epithelial cells, IL-36 is (Halim et al. 2014). Notably, IL-33-expanded upregulated during psoriasis, and in bronchial ILC2s also produce the tissue repair and growth cells during viral or bacterial infection (Boutet factor amphiregulin (AREG), an epidermal et al. 2016). Unlike other IL-1 family members, growth factor (EGF) receptor ligand (Monticelli IL-37 expression can be induced by the anti- et al. 2011). IL-5 and IL-13, secreted by both Th2 inflammatory cytokine transforming growth cells and ILC2s, contribute to the recruitment of factor (TGF)-β (Nold et al. 2010). However, in eosinophils, which amplifies allergic airway in- peripheral blood monocytic cells and dendritic flammation (Yamaguchi et al. 1988; Pope et al. cells, IL-37 expression was also elevated by 2001; Nussbaum et al. 2013). In allergic asthma, stimulation through TLRs (Sharma et al. 2008; eosinophils are a major source of IL-4 and me- Nold et al. 2010). Expression of the little-known diate inflammation by releasing cytotoxic gran- IL-38 cytokine is restricted to few tissue sites, ules and lipid mediators that induce tissue dam- including skin and the spleen (Lin et al. 2001). age and bronchoconstriction (Kita 2011). IL-33 In summary, while IL-1 family cytokines are contributes to this process not only by mediat- expressed by a wide variety of tissues, they are ing the expansion of Th2 cells and ILC2s, but usually released only in response to “danger” additionally it can promote the differentiation of signals. eosinophils from CD117+ progenitors in an IL-

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Treg cells Tissue repair • Lung Th2 cells • Intestine • CNS • Skeletal muscle

Endothelial cells Tissue homeostasis Eosinophils Epithelial cells • Adipose tissue Mast cells • Intestine Dendritic cells • Uterus IL-33 Macrophages • Skin

CD8+ T cells Pathogen defense • Helminths • DNA and RNA viruses

ILC2s

M2 macrophages

Figure 1. Illustration shows the diverse cellular sources of interleukin (IL)-33, sensing of IL-33 by adaptive and innate immune cells, and the plethora of immunological and nonimmunological functions regulated by IL-33 to preserve immune and tissue homeostasis. CNS, Central nervous system; Th, T helper; Treg, regulatory T cells; ILC2s, type 2 innate lymphoid cells.

5-dependent manner (Stolarski et al. 2010). Eo- IL-33 AND Th1 RESPONSES sinophils in the airway express high levels of ST2 and respond to IL-33 secreted by lung epithelial Intracellular pathogens, including bacteria and cells (Kurowska-Stolarska et al. 2008). IL-33 not viruses, induce type 1 inflammation executed by only promotes differentiation of eosinophils, CD4+ and CD8+ T cells, macrophages, and B but also improves their function by augmenting cells. Recent studies have shown that IL-33 is the expression of IL-13, IL-6, CCL-17, and TGF- also involved in the establishment of Th1 in- β (Stolarski et al. 2010). IL-33 also induces the flammation and cytotoxic T-cell responses. differentiation and expansion of alternatively During lymphocytic choriomeningitis virus activated M2 macrophages, which express the (LCMV) infection, Th1 cells were found to ex- IL-4R, secrete CCL-24 and CCL-17 and coop- press ST2 in a T-bet- and signal transducers and erate with Th2 cells and eosinophils in airway activators of transcription (STAT)4-dependent inflammation (Kurowska-Stolarska et al. 2009). manner (Baumann et al. 2015). ST2 expression In agreement with its role in promoting and in Th1 cells, however, was transient compared to amplifying airway inflammation, mutations in the constitutive high levels observed in Th2 cells. Il33 and Il1rl1 (encoding ST2) are closely asso- ST2 contributed to the expansion of antigen- ciated with increased asthma risk (Gudbjartsson specific Th1 cells and promoted the expression et al. 2009; Moffatt et al. 2010). Taken together, of Th1 transcription factor T-bet (Baumann IL-33 initiates and amplifies Th2 inflammation et al. 2015). Another study found that IL-33 by promoting the differentiation, maintenance, induced Th1 cell differentiation by potentiating and function of Th2 cells, ILC2s, eosinophils, the activity of the Th1-polarizing cytokine IL- and alveolar macrophages (Fig. 1; Table 1). 12; however, IL-33 by itself was unable to pro-

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IL-33 and IL-1 Families of Cytokines

Table 1. Cytokine and receptor nomenclature of the interleukin (IL)-1 family and their functions mediated by immune cells. Cytokine Receptor Coreceptor Immune cell target Function IL-33 ST2 IL-1RAcP Th2 and Th1 cells, Treg cells, Type 1 and type 2 immunity, macrophages, CD8+ T cells, maintenance of organismal eosinophils, ILC2s, NK cells, NKT metabolism, thermogenesis, tissue cells repair IL-1α IL-1R1 IL-1RAcP Macrophages Sterile inflammation IL1-R2 IL-1β IL-1R1 IL-1RAcP Th17 cells, Th1 cells, ILC1s, CNS inflammation, type 1 immunity, IL1-R2 regulatory B cells gut homeostasis IL-18 IL-18Rα IL-18Rβ Th1 cells, CD8+ T cells, NK cells, Type 1 immunity ILC1s IL-36α, IL-1Rrp2 IL-1RAcP CD8+ T cells, NK cells, and γδ T cells Type 1 immunity, antitumor β, γ immunity IL-37 IL-18Rα Dendritic cells, macrophages, Treg Immune suppression cells IL-38 IL-1Rrp2 T cells Immune suppression IL-1RA IL-1R1 Macrophages, dendritic cells, Th17 Restrains inflammation IL-36RA IL-1Rrp2 Unknown Restrains inflammation Th, T helper; Treg cell, regulatory T cell; ILC2, type 2 innate lymphoid cell; NK, natural killer; NKT cell, natural killer T cell; CNS, central nervous system.

mote Th1 differentiation (Komai-Koma et al. is also a reservoir for multiple pro- and anti- 2016). IL-33 was also found to induce ST2 ex- inflammatory immune cells (Cipolletta et al. pression in CD8+ T cells in vitro and augmented 2011; Wensveen et al. 2015). Obesity leads to TCR-signaling-dependent interferon (IFN)-γ the expansion of proinflammatory immune production (Yang et al. 2011). In line with these cells, which induce insulin resistance and, sub- findings, during infection with an acute strain of sequently, type 2 diabetes (Cipolletta et al. 2011; the LCMV, IL-33 promoted the clonal expan- Wensveen et al. 2015). Over the last few years, it sion and function of effector CD8+ T cells (Fig. has become apparent that IL-33 plays a central 1) (Bonilla et al. 2012). IL-33 also expanded a role in VAT homeostasis. IL-33 facilitates the population of ST2+ natural killer T (NKT) cells differentiation and maintenance of Foxp3+ and augmented TCR signaling and IL-12-de- Treg cells and ILC2s in the VAT, both of which pendent expression of IFN-γ (Bourgeois et al. play critical roles in limiting VAT inflammation 2009). Similarly, IL-33 also induced IFN-γ pro- and maintaining insulin sensitivity (Table 1) duction in NK cells and promoted the NK cell (Feuerer et al. 2009; Cipolletta et al. 2012; Bres- response against murine cytomegalovirus (Na- toff et al. 2015; Vasanthakumar et al. 2015). Treg bekura et al. 2015). Overall, these data suggest cells are a subset of CD4+ T cells that potently that IL-33 is a potent but context-specificam- suppress autoreactive and inflammatory T cells. plifier of Th1 inflammation; however, its precise The majority of Treg cells develops in the thy- role needs to be further evaluated. mus; however, they undergo further differentiation and diversification in the periphery, which allows them to acquire full suppressive function IL-33 IN ORGANISMAL METABOLISM and the ability to enter nonlymphoid tissues, Visceral adipose tissue (VAT) is an important including the VAT (Burzyn et al. 2013a; Teh endocrine organ that secretes soluble factors et al. 2015). VAT Treg cells co-opt the adipose such as leptin and adiponectin to regulate or- tissue transcription factor PPAR-γ for their dif- ganismal metabolism (Coelho et al. 2013). VAT ferentiation and maintenance (Cipolletta et al.

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A. Vasanthakumar and A. Kallies

2012). While development and survival of Treg IL-33 treatment (Molofsky et al. 2015). Howev- cells in most tissues is strictly dependent on IL-2 er, such a mechanism has not yet been sup- (Liston and Gray 2014), VAT-resident Treg cells ported by additional studies. IL-33 also directly in addition require IL-33 for their survival and acted on adipose tissue to induce the expression maintenance (Vasanthakumar et al. 2015). VAT of UCP-1 by an unconventional mechanism as Treg cell numbers significantly decrease in the discussed later (Odegaard et al. 2016). Thus, absence of IL-33 signaling. In vitro, IL-33 facil- while it is clear that IL-33 plays a central role itated population expansion of VAT Treg cells in maintaining adipose homeostasis, precisely even in the absence of IL-2 or TCR signaling how IL-33-responsive cells and IL-33-depen- (Vasanthakumar et al. 2015). IL-33 expression dent mechanisms cooperate in the adipose to in the adipose tissue increased with age, which maintain tissue health remains to be elucidated. also correlates with an increase in VAT Treg Of note, IL-18 also plays a protective role in cells, suggesting that IL-33 is the rate-limiting obesity (Lee et al. 2016; Murphy et al. 2016), cytokine for Treg-cell expansion in the adipose while IL-1β drives adipose tissue inflammation tissue. In keeping with this notion, administra- and insulin resistance (Lee et al. 2016). tion of IL-33 expanded Treg cells specifically in the adipose tissue (Kolodin et al. 2015; Molof- IL-33 IN TISSUE HOMEOSTASIS AND REPAIR sky et al. 2015; Vasanthakumar et al. 2015). Obesity leads to the decline of VAT Treg cell As outlined earlier, IL-33 is released predomi- numbers, which coincides with exacerbation nantly by inflamed or injured tissue. Remark- of inflammation in the VAT and development ably however, IL-33 is also involved in tissue of insulin resistance (Fig. 1) (Feuerer et al. 2009; repair, a mechanism that is likely to have evolved Vasanthakumar et al. 2015). When adminis- as a feedback to restrain tissue damage. IL-33- tered to obese mice, IL-33 rescued Treg cell dependent Treg-cell-mediated tissue repair has numbers in the VAT, which coincided with sup- been demonstrated in skeletal muscle and the pression of inflammation and improved glucose lung (Fig. 1). Skeletal muscle regeneration crit- tolerance (Han et al. 2015; Vasanthakumar et al. ically depends on a self-renewing population of 2015). Besides facilitating survival and prolifer- cells called satellite cells. Upon injury, satellite ation, IL-33 also enhances the expression of cells proliferate and differentiate into new my- GATA3 and Foxp3 in VAT Treg cells, and pre- ofibers or fuse to existing ones and promote serves expression of PPAR-γ, suggesting a piv- regeneration. While inflammatory CD4+ and otal role for IL-33 in preserving VAT Treg cell CD8+ T cells impede this process (Tidball and function and phenotype (Vasanthakumar et al. Villalta 2010), IL-33-dependent Treg cells 2015). maintain an environment conducive for satellite IL-33 is also a critical growth factor for VAT cell differentiation and muscle regeneration ILC2s, which promote the conversion of white (Burzyn et al. 2013b). Treg cells that reside and adipose tissue to brown adipose tissue (BAT) expand in the muscle after injury critically de- (Brestoff et al. 2015; Lee et al. 2015). BAT is pend on IL-33 (Kuswanto et al. 2016). Similar to critically important for thermogenesis of new- the injured muscle, IL-33-dependent Treg cells borns but also contributes to weight loss as it play an important role in restraining inflamma- generates heat from chemical energy (calories). tion in the gastrointestinal tract (Schiering et al. ILC2-derived methionine–enkephalin peptides 2014). Consistent with this finding, Treg cells induce the expression of brown adipocyte factor deficient for ST2 could not control experimental uncoupling protein-1 (UCP-1), required for colitis. IL-23, a cytokine known to drive intesti- thermogenesis (Brestoff et al. 2015). It has also nal inflammation and inflammatory bowel dis- been proposed that ILC2s were involved in me- ease, inhibited the function of IL-33 (Schiering diating the IL-33-dependent VAT Treg cell ex- et al. 2014). pansion, as VAT Treg cells from IL-5-deficient Finally, IL-33 has been shown to induce ex- mice, which lacked ILC2s, failed to expand upon pression of AREG in Treg cells. This function

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IL-33 and IL-1 Families of Cytokines

was shown to play a role in Treg-cell-mediated 2016). Thus, while IL-33 maintains tissue ho- lung tissue repair after influenza virus infection. meostasis by augmenting population expansion Lung epithelial cell–derived IL-33 induced up- and function of immune cells that facilitate tis- regulation of AREG in lung-resident Treg cells, sue repair, it can also drive tumor growth (Fig. 1; which facilitated repair of damaged lung epithe- Table 1). lium and improved lung function after resolu- tion of the infection (Fig. 1) (Arpaia et al. 2015). IMMUNE REGULATION BY OTHER IL-1 AREG is also highly expressed in Treg cells in FAMILY MEMBERS the adipose tissue (Vasanthakumar et al. 2015), suggesting that tissue repair is a common IL-33- In addition to IL-33, other IL-1 family cytokines induced mechanism of action for Treg cells re- play critical roles in the differentiation and siding in nonlymphoid tissues. Indeed, IL-33 function of multiple immune cells. IL-18 was also induces AREG expression in ILC2s to pro- originally identified as a costimulator of IFN-γ mote tissue repair in the lung and intestinal ep- production and subsequently established to con- ithelia (Monticelli et al. 2011, 2015). Treatment tribute to Th1 differentiation (Yoshimoto et al. of mice with recombinant IL-33 increased the 1998). IL-18 was also required for the efficient expression of tight junction proteins claudin1 production of IFN-γ and TNF in antigen-specif- and mucin and improved intestinal integrity, ic CD8+ T cells, suggesting a prominent role for thereby preserving barrier function (Monticelli IL-18 in viral defense (Denton et al. 2007). Sim- et al. 2015). IL-33 also plays an important role in ilarly, IL-18 promotes IFN-γ production in NK limiting brain tissue damage. Upon brain injury, cells and ILC1 (Table 1) (Chaix et al. 2008; Ma- damaged oligodendrocytes release IL-33, which loy and Uhlig 2013). acts on microglial cells and astrocytes to secrete IL-1β promotes the differentiation of IL-17- chemokines and cytokines to attract neuropro- producing Th17 cells and γδ T cells in vivo and tective M2 macrophages that facilitate neural have been implicated in autoimmune and in- tissue repair (Gadani et al. 2015). Similarly, flammatory diseases that affect the CNS (Chung ILC2s that reside in the meninges are activated et al. 2009; Sutton et al. 2009). IL-6 induced IL- by IL-33 secreted upon CNS injury and contrib- 1R1 expression on CD4+ T cells, thereby facili- ute to limiting CNS injury (Gadani et al. 2017). tating Th17 differentiation and induction of Finally, IL-33 has also been shown to induce the experimental autoimmune encephalomyelitis expansion of IL-10-producing B cells, thereby (Chung et al. 2009). Notably, Th17 cells them- limiting inflammation in the intestine and pro- selves are equipped with NLRP3 and caspase-8, tecting from inflammatory bowel disease (Satt- allowing for the secretion of bioactive IL-1β,cre- ler et al. 2014). ating an autocrine loop that facilitates differen- Inflammatory mediators within the tumor tiation of Th17 cells (Martin et al. 2016). IL-1β microenvironment can either promote an anti- also contributes to Th1 inflammation and cyto- tumor immune response or support tumor toxic T-cell differentiation by activating den- pathogenesis. In keeping with this notion, IL- dritic cells to produce IL-12 (Wesa and Galy 33 plays a context-dependent role in tumor bi- 2001). Interestingly, IL-1β cooperates with IL- ology where it can be protective or deleterious. 33 in ILC2 biology. While IL-33 is critical for For example, IL-33 facilitates the expansion of ILC2 cell differentiation, IL-1β is required for NK cells and cytotoxic CD8+ T cells to promote their activation. IL-1β also induces the expres- tumor eradication (Gao et al. 2015). On the oth- sion of IL-12 receptor, which facilitates T-bet er hand, IL-33 augments tumor growth by pro- expression and transdifferentiation to ILC1 lin- moting colorectal cancer cell stemness (Fang eage cells (Ohne et al. 2016). Finally, gut micro- et al. 2017) and metastasis in lung cancer biota–induced IL-1β is required for the differen- (Wang et al. 2016a). The multifaceted role of tiation of regulatory B cells, which contribute to IL-33 in the tumor environment was reviewed immune homeostasis by producing the anti-in- in more detail recently (Wasmer and Krebs flammatory cytokine IL-10 (Rosser et al. 2014).

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Several lines of evidence suggest that IL-1α by caspases and proteases to release bioactive and IL-1β promote tumorigenesis by inducing forms (Garlanda et al. 2013). For example, IL- the expression of growth factors that facilitate 1β is secreted as a pro-IL-1β, which is cleaved by tumor growth and metastasis. IL-1 induces the caspase-1 to release the bioactive IL-1β into cir- expression of several tumorigenic and metastat- culation. While most immune cells express cas- ic mediators, such as matrix metalloproteinases pase-1, its activity is regulated by the inflam- (MMPs), vascular endothelial growth factor masome NLRP3. Neutrophil-secreted enzymes (VEGF), IL-8, IL-6, TNF, and TGF-β. Tumor elastase and proteinase-3 also cleave pro-IL-1β tissue–derived IL-1β itself attracts immune cells, efficiently to generate the bioactive forms. In including macrophages and neutrophils, which contrast, the IL-1α precursor, which is released further produce IL-1β to promote angiogenic upon necrosis of source tissues, is readily avail- response, tumor invasiveness, and metastasis able for the induction of inflammation, as it (Apte et al. 2006; Perrier et al. 2009; Voronov can activate signaling directly by binding to its et al. 2014). In contrast, IL-36γ, which is also receptor. highly expressed in the tumor environment, Similar to IL-1β, IL-18 is translated as a 24- plays a protective role in cancer by polarizing kDa protein, which then is cleaved by NLRP3- CD8+ T cells, NK cells, and γδ T cells to produce activated caspase-1 to become 17-kDa active IL- IFN-γ and establishes a conducive setting for 18. Thus, NLRP1-deficient mice also have re- tumor eradication (Wang et al. 2015). Th1 cells duced amounts of active IL-18, manifesting in have also been shown to express IL-36R, signal- spontaneous obesity (Murphy et al. 2016). Pro- ing through which synergized with IL-12 in Th1 IL-18 can be also cleaved by neutrophil-derived differentiation in vivo (Vigne et al. 2012). proteases and proteinase-3 to generate the ac- The anti-inflammatory cytokine of the IL-1 tive form. The biological activity of IL-36 also family, IL-37, plays a role in restraining activa- requires posttranslational processing (Towne tion of antigen-specific T cells by suppressing et al. 2011); however, precisely how pro-IL-36 dendritic cell activation and limiting the expres- is cleaved is unclear. Similarly, the mechanisms sion of proinflammatory cytokines IL-1β, IL-6, underlying IL-37 processing are unknown, al- and IL-12 (Luo et al. 2014). IL-37 also repressed though they are likely to involve caspase-1 (Li the expression of IL-6 in LPS-induced macro- et al. 2015). phages, suggesting its role in dampening innate IL-33, unlike most other members of the immune responses (Li et al. 2015). Finally, IL-37 family, is released by necrotic cells as a 29-kDa promoted the suppressive properties of Treg full-length protein that has bioactivity and does cells by inducing up-regulation of IL-10, TGF- not require proteolytic processing (Martin and β, and CTLA-4 (Wang et al. 2016b). Thus, IL-1 Martin 2016). Although originally believed to be cytokines play diverse roles in infection autoim- processed by caspase-1, later studies revealed munity and cancer. caspase-1 to be redundant for IL-33 activity (Talabot-Ayer et al. 2009). In contrast, proteases secreted by neutrophils, macrophages, and REGULATION OF EXPRESSION OF mast cells cleave the amino-terminal end of hu- ACTIVE IL-33 AND OTHER IL-1 FAMILY man IL-33, resulting in a 10-fold increase in CYTOKINES activity (Lefrancais et al. 2012). On the other Production of IL-1 family members is tightly hand, caspase-3 and -7 released by apoptotic regulated at several levels. Notably, all IL-1 fam- cells can effectively cleave and inactivate IL-33. ily members with the exception of IL-1 receptor Thus, the expression of the active forms of IL-1 antagonist (IL-1Ra) are translated without a sig- family cytokines is controlled by multiple post- nal peptide that would be required for active translational mechanisms that have evolved to secretion via the endoplasmic reticulum and balance the fine line between the beneficial and Golgi apparatus (Sims and Smith 2010; Afonina detrimental functions of the members of this et al. 2015). Therefore, they need to be cleaved cytokine family.

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IL-33 and IL-1 Families of Cytokines

REGULATION OF IL-33 AND IL-1 FAMILY Proximal IL-1 family signaling is regulated SIGNALING tightly by decoy and antagonistic receptors (Sims and Smith 2010; Garlanda et al. 2013). Most members of the IL-1 family signal by bind- For example, the IL-33 receptor is generated in ing to heterodimeric receptors. IL-33, IL-1α, IL- two distinct forms that differ functionally: 1β, and IL-36 utilize a common receptor chain membrane-bound ST2 that allows functional called IL-1RAcP. IL-1α, IL-1β, and IL-1RA share IL-33 signaling and a shorter soluble form that yet another common receptor chain, IL-1R1. In sequesters available IL-33 (Yanagisawa et al. contrast, ST2 is exclusively used by IL-33, while 1993; Garlanda et al. 2013; Martin and Martin IL-1Rrp2 is specific to IL-36. IL-36RA is an IL- 2016). Notably, increased soluble ST2 is a prog- 36Rantagonistthathasmorethan50%similarity nostic marker for several inflammatory diseases to IL-1RA. IL-1α and IL-1β can also signal by (Kim et al. 2015). Similarly, the soluble receptor binding to IL-1R2. IL-18 and IL-37 bind and isoform of IL-1R2 can bind to IL-1β extracellu- signal through a heterodimeric receptor com- larly and render it unavailable for signaling. IL- posed of IL-18Rα and IL-18Rβ (Fig. 2; Table 1) 1R signaling is also inhibited by the IL-1R (Garlanda et al. 2013). Despite the diversity in antagonist, IL-1RA, which competes with IL- receptor recognition, all IL-1 family receptors 1β for IL-1R1 receptor binding (Aksentijevich possess a cytoplasmic Toll-IL-1R (TIR) domain et al. 2009). Furthermore, soluble IL-1R2 and and initiate a common signaling cascade, which IL-1RAcP can also bind to pro-IL-1β efficiently is similar to TLRs and requires the adaptor and prevent its proteolytic processing. Similar Myd88 (O’Neill 2000). Signaling downstream mechanisms exist for other IL-1-like cytokines, of Myd88 involves IRAKs, TRAF6, and TAK1, for example, for IL-36, through expression of an leading to the activation of Janus kinase (JNK), antagonist receptor for IL-36, and for IL-18 extracellular signal-regulated kinase (ERK), and through the expression of IL-18-binding protein mitogen-activated protein kinase (MAPK) path- (IL-18BP), which prevents IL-18 interaction ways.Eventually,transcriptionfactors, including with the receptor (Fig. 2; Table 1) (Sims and RelA/p65 (nuclear factor [NF]-κB) and c-Jun es- Smith 2010; Garlanda et al. 2013). tablish the transcriptional program activated by In addition to the above-described mecha- IL-1 family members (O’Neill and Greene 1998). nisms that control the availability of IL-1-like

Negative regulators/ antagonist sST2 IL-1RA IL-36RA IL-37

Positive regulators/ IL-1a IL-36a agonist IL-1b IL-36b IL-33 IL-38 IL-36g IL-18 IL-1b

TIR-domain ST2 IL-1R1 IL-1R2 IL-18Ra IL-18Rb IL-1Rrp2 IL-1RAcP IL-1RAcP IL-1RAcP IL-1RAcP

IL-33R IL-1R IL-36R IL-18R

Figure 2. A schematic representation of interleukin (IL)-1 family receptors, coreceptors, ligands, and negative regulators. TIR, Toll-IL-1R.

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cytokines, the expression of some receptors is regulated by nuclear IL-1α includes prolifera- tightly governed by transcriptional mecha- tion, cell migration, apoptosis, and expression nisms. This is particularly well known for ST2, of cytokines, including IL-18 and TNF (Gar- the expression of which is controlled by the Th2 landa et al. 2013; van de Veerdonk and Netea lineage–determining transcription factor Gata3 2013). Nuclear IL-1α also interacts with NF-κB (Hayakawa et al. 2005). Similarly, ST2 expres- transcription factors to regulate gene expression sion in ILC2s (Hoyler et al. 2012; Mjosberg et al. and, similar to IL-33, facilitates the splicing of 2012) and colonic Treg cells (Schiering et al. prosurvival molecule Bcl-xL (Pollock et al. 2014) is regulated by Gata3. In contrast, Th1 2003). Finally, IL-37 was shown to translocate cells expressed ST2 in a T-bet- and STAT4-de- to the nucleus and to repress the expression of pendent manner (Baumann et al. 2015). ST2 inflammatory genes in LPS-treated macro- expression on Treg cells also required the TCR phages (Sharma et al. 2008). signaling-induced transcription factor IRF4 and its binding partner BATF (Vasanthakumar et al. CONCLUDING REMARKS 2015). A recent study has shown that PPAR-γ is required for efficient ST2 expression on Th2 IL-1 has long been known to play a central role cells (Chen et al. 2017). It remains to be seen in inflammation. More recently, IL-33 has whether PPAR-γ contributes to regulation of emerged as another crucial regulator of immu- ST2 expression in other cell types. nity and tissue homeostasis (Fig. 1). However, while substantial advances were made over the last decade, there are many aspects of the biol- NUCLEAR FUNCTIONS OF IL-33, IL-1α, ogy of IL-1 family cytokines that remain unex- AND IL-37 plored. Processing of the procytokine forms into Unlike other cytokines, some IL-1 family mem- biologically active forms is a key and the fore- bers are known to have nuclear functions. IL-33, most regulatory mechanism in IL-1 biology. Yet, IL-1α, and IL-37 possess a nuclear localization the precise mechanism by which IL-33 is cleaved sequence (NLS) that facilitates nuclear entry. IL- or the exact function of long versus short forms 33 also possesses an amino-terminal homeodo- of IL-33 in immunity and inflammation are still main like helix–turn–helix (HTH) DNA-bind- a matter of intense debate. It is also incompletely ing domain (Carriere et al. 2007). Nuclear IL-33 known how specificity of signaling is achieved can act both as a transcriptional activator and by members of the IL-1 cytokine family, given repressor in a context-specific manner. It can that the receptor chains are shared by many of interact with histone H2A and H2B and regulate the IL-1-like cytokines. For example, it is un- chromatin architecture and partner with the clear whether ST2 or IL-1R compete for IL- methyltransferase SUV39H1 to facilitate repres- 1RAcP or interact with different affinities. In sion of genes (Carriere et al. 2007). Furthermore, such a scenario, ST2 or IL-1R may sequester IL-33 can cooperate with NF-κB transcription IL-1RAcP and thereby limit signaling through factors p65/RelA and p50 and sequester them to the other receptor. This may be critical when the cytoplasm, thereby, preventing the expres- designing blocking antibodies for a particular sion of inflammatory genes (Ali et al. 2011). cytokine as such antibodies may affect the activ- Although not a nuclear function, a recent study ity of other cytokines that share the receptor has also shown that intracellular IL-33 can reg- chain. Similarly, while it is clear that soluble ulate the splicing of uncoupling protein-1 ST2 can limit the signaling of IL-33, it is un- (UCP-1) gene in adipocytes, thereby regulating known how the expression of the soluble and thermogenesis and brown fat differentiation membrane-bound forms of ST2 is regulated. (Odegaard et al. 2016). Similar to IL-33, IL-1α Importantly, although IL-33 is localized in the can also translocate to the nucleus and activates nucleus, its role in transcription has not been transcription by interacting with chromatin studied fully. It is also unclear whether the IL- (Garlanda et al. 2013). The range of functions 33 released extracellularly by necrotic or in-

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Interleukin (IL)-33 and the IL-1 Family of Cytokines−−Regulators of Inflammation and Tissue Homeostasis

Ajithkumar Vasanthakumar and Axel Kallies

Cold Spring Harb Perspect Biol published online November 3, 2017

Subject Collection Cytokines

Interleukin (IL)-33 and the IL-1 Family of Cytokines Interferon γ and Its Important Roles in Promoting −−Regulators of Inflammation and Tissue and Inhibiting Spontaneous and Therapeutic Homeostasis Cancer Immunity Ajithkumar Vasanthakumar and Axel Kallies Elise Alspach, Danielle M. Lussier and Robert D. Schreiber Targeting IL-10 Family Cytokines for the Inflammasome-Dependent Cytokines at the Treatment of Human Diseases Crossroads of Health and Autoinflammatory Xiaoting Wang, Kit Wong, Wenjun Ouyang, et al. Disease Hanne Van Gorp, Nina Van Opdenbosch and Mohamed Lamkanfi Cytokine-Mediated Regulation of CD8 T-Cell Innate Lymphoid Cells (ILCs): Cytokine Hubs Responses During Acute and Chronic Viral Regulating Immunity and Tissue Homeostasis Infection Maho Nagasawa, Hergen Spits and Xavier Romero Masao Hashimoto, Se Jin Im, Koichi Araki, et al. Ros Cytokines in Cancer Immunotherapy T Helper Cell Differentiation, Heterogeneity, and Thomas A. Waldmann Plasticity Jinfang Zhu The Tumor Necrosis Factor Family: Family Development, Diversity, and Function of Dendritic Conventions and Private Idiosyncrasies Cells in Mouse and Human David Wallach David A. Anderson III, Kenneth M. Murphy and Carlos G. Briseño The Interferon (IFN) Class of Cytokines and the Cytokines and Long Noncoding RNAs IFN Regulatory Factor (IRF) Transcription Factor Susan Carpenter and Katherine A. Fitzgerald Family Hideo Negishi, Tadatsugu Taniguchi and Hideyuki Yanai

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Role of the β Common (βc) Family of Cytokines in Negative Regulation of Cytokine Signaling in Health and Disease Immunity Timothy R. Hercus, Winnie L. T. Kan, Sophie E. Akihiko Yoshimura, Minako Ito, Shunsuke Chikuma, Broughton, et al. et al. Interleukin (IL)-12 and IL-23 and Their Conflicting Cancer Inflammation and Cytokines Roles in Cancer Maria Rosaria Galdiero, Gianni Marone and Alberto Juming Yan, Mark J. Smyth and Michele W.L. Teng Mantovani

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